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Progranulin, a moderator of estrogen/estrogen receptor α binding, regulates bone homeostasis through PERK/p-eIF2 signaling pathway

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Abstract

Under normal conditions, the human body employs the synergistic action of osteoblasts and osteoclasts to maintain a dynamic balance between bone formation and resorption. Bone homeostasis plays a very important role in the process of bone formation. Various bone diseases can occur if bone homeostasis is disrupted. In this study, the serum estrogen levels were significantly increased in the granulin (GRN)–deficient mice and PGRN regulates the binding of estrogen and estrogen receptor α (ERα) and then affects estrogen’s ability to regulate bone formation and resorption. In addition, this study also explored the role that PGRN plays in regulating bone homeostasis by affecting the binding of estrogen and estrogen receptors through the protein kinase R-like endoplasmic reticulum kinase/phosphorylation of the eukaryotic initiation factor 2 signaling pathway. In summary, we confirmed the important role of PGRN in regulating the estrogen (E2)/ERα signal in maintaining bone homeostasis. Our findings may provide a new strategy for the treatment of osteoporosis and maintaining bone homeostasis.

Key messages

  • PGRN is a molecular regulator of the binding of E2 and ERα signal in maintaining bone homeostasis.

  • PGRN plays in regulating bone homeostasis through the PERK/p-eIF2α signaling pathway.

  • The best therapeutic effect of PGRN in osteoporosis is associated with different concentration of E2.

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Authors’ information

We are committed to studying ER stress, autophagy, and their relation to bone development and bone-associated diseases. Y.Y.Y, N.B.F, Y.M.P., and G.N.N. were doctoral students; L.L. was a master’s student; M.T.F. was a postdoctoral researcher; R.J., X.L.L, and F.J.G. were teachers and researchers.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

PGRN:

Progranulin

GRN:

Granulin

ERα:

Estrogen receptor α

PERK:

Protein kinase RNA (PKR)–like ER kinase

p-eIF2α:

Phosphorylation of eukaryotic initiation factor 2 α

E2:

Estrogen

OVX:

Ovariectomy

XBP1:

X-box binding protein 1

ATF4:

Activating transcription factor 4

ER:

Endoplasmic reticulum

BMP-2:

Bone morphogenetic protein-2

RUNX2:

Runt-related transcription factor 2

OPG:

Osteoprotegerin

DMP1:

Dentin matrix acidic phosphoprotein 1

NFATc1:

Nuclear factor of activated T cells, cytoplasmic 1

ACP5:

Acid phosphatase 5

CTSK:

Cathepsin K

RANK:

Receptor activator of NF-κB

RANKL:

RANK ligand

M-CSF:

Macrophage colony-stimulating factor

TRAP:

Tartrate-resistant acid phosphatase

VMD:

Visual molecular dynamics

CRISPR-Cas9:

Clustered regularly interspaced short palindromic repeats-associated protein 9

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Acknowledgements

All experiments are completed on the experimental platform provided by the Core Facility of Development Biology of Basic Medical College (Chongqing Medical University).

Funding

Our experiments were financially supported by the Natural Science Foundation of China (No.81672209, No.81871769); Chongqing Science and Technology Bureau (cstc2020jcyj-msxmX0175); and Chongqing Human Resources and Social Security Bureau (2018–389).

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Author notes

  1. Yuyou Yang and Naibo Feng contributed equally to this work

Authors and Affiliations

  1. Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing, 400016, China

    Yuyou Yang, Naibo Feng, Li liang, Yiming Pan, Nana Geng, Mengtian Fan, Xiaoli Li & Fengjin Guo

  2. Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, China

    Rong Jiang

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Contributions

All authors participated in the design, interpretation of the studies and analysis of the data, and review of the manuscript; all authors approved the final version to be published. Y.Y.Y, N.B.F, L.L., Y.M.P., G.N.N., M.T.F., and R.J. conducted the experiments; N.B.F, Y.Y.Y, L.L., and F.J.G. analyzed and interpreted the data; Prof. Fengjin Guo designed the manuscript and had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors have read and approved the final manuscript prior to submission.

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Correspondence to Fengjin Guo.

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This study was approved and granted by the Ethics Committee of Chongqing Medical University (March 23, 2021).

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Yang, Y., Feng, N., liang, L. et al. Progranulin, a moderator of estrogen/estrogen receptor α binding, regulates bone homeostasis through PERK/p-eIF2 signaling pathway. J Mol Med 100, 1191–1207 (2022). https://doi.org/10.1007/s00109-022-02233-z

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  • DOI: https://doi.org/10.1007/s00109-022-02233-z

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